E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alzheimer's disease Down syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Alzheimer's disease Down syndrome |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013616 |
E.1.2 | Term | Down's syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The aims of the study are to gather the data needed to design a full-scale multi-centred RCT of oral simvastatin 40mg a day.
The principal research questions are:
What are the: (1) trial recruitment/retention rates and recruitment sources, (2) rates of tolerability/safety of oral simvastatin 40mg a day, (3) most sensitive instruments to detect early cognitive decline in adults with Down syndrome, and (4) perceptions of adults with Down syndrome and their carers on deciding whether to participate, on randomisation, and their experience of the assessments?
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E.2.2 | Secondary objectives of the trial |
The secondary reserach questions are:
(5) what are the distributions of the primary (cognitive decline) and key secondary (adative behavior, general health/quality of life, service use, carer strain) outcome measures that would be used in a definitive RCT, and what are the sample size implications of these distributions, (6) is Aβ42/Aβ40 a biomarker for cognitive decline, and (7) do the results support proceeding to a full RCT?
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Qualitative sub-study "Your views count", included in the main protocol version 2, dated 26.6.11. |
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E.3 | Principal inclusion criteria |
(1) Down syndrome. (2) Aged ≥50.
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E.4 | Principal exclusion criteria |
(1) No consent obtained. (2) Unable to comply with the protocol, including providing blood or saliva for baseline APO E e4 measurement, and venous or capillary blood for cholesterol measurement. (3) Dementia at baseline (as the study is investigating primary prevention). (4) Diabetes (as this is an indication for a prescription of a statin). (5) Clinically evident atherosclerotic disease (as this is an indication for a prescription of a statin). (6) Being at risk for cardiovascular disease (as this is an indication for a prescription of a statin). (7) Liver disease. (8) Chronic renal insufficiency. (9) Being prescribed: a) statin, b) fibrates, c) nicotinic acid, d) cyclosporine, e) azole antifungal, f) itraconazole, g) ketoconazole, h) macrolide antibiotics, i) erythromycin, j) clarithromycin, k) fusidic acid, l) HIV protease inhibitors, m) nefazodone, n) verapamil, o) amiodarone, p) warfarin. (10) Having previously had a statin serious adverse reaction. (11) Unable or unwilling to avoid consumption of grapefruit juice. (12) Excessive alcohol use (>21 units/week for men, or >14 units/week for women).
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E.5 End points |
E.5.1 | Primary end point(s) |
1: Feasibility (1) The numbers screened and recruited each month over the 6 month recruitment period. (2) The retention of participants in the study after 12 months. (3) The percentage of the total recruited from each source, and the number of contacts with each source to achieve this. The source will be identified at the initial telephone call to assess suitability to invite the person to participate. The number of contacts will be identified through the researcher and the SPCRN recording each one on a contact recording sheet. (4) The number recruited per base general population size. Base population size is that for Greater Glasgow and Clyde, Lothian, and Tayside Health Board area, according to Scottish government data.
2: Tolerability and safety (1) Compliance will be assessed by counting returned tablets every 3 months. (2) Blood will be taken to measure muscle enzyme levels 6-12 weeks after starting the simvastatin/placebo. (3) 3 monthly interviews will be conducted using the AE schedule, in addition to recording spontaneously reported AEs using the standard sponsor’s AE protocol.
3: Identification of the most suitable cognitive measures (1) Based on published data of measures of cognitive decline in Down Syndrome, we have identified eight tests considered most likely to be sensitive to change. The tests are in the domains of memory, attention and executive functioning. Scores at baseline and after 12 months of simvastatin/placebo will be compared for each of these measures to identify which show the greatest degree of change over the period, and have the greatest utility across the full range of intellectual disabilities (i.e. the tests that are completed by the highest number of participants). This will determine the primary outcome measure for the full-scale study.
4: Participant/carer perceptions (1) Key themes will be identified from the semi-structured interviews to improve our understanding of participants' perspectives about research participation, randomisation and the experience of having the assessments.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1: Effect size after 12 months simvastatin/placebo (1) cognitive decline (2) skill decline (3) general health/quality of life (4) service use and social changes
2: Biomarkers (1) Abeta40/Abeta42 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Each participant completes at the end of the 12 month assessment for all outcomes, except safety, for which completion is 30 days after the last dose of simvastatin/ placebo. The trial itself ends 24 months after it starts which will be 2 months after the final assessment, allowing time for analyses and dissemination. The entire study would be stopped prematurely if the ChI/sponsor interpreted advice from the independent DMEC to show detrimental effects on cognition, death, or SUSARs |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |